Ready-to-use co-solvents pharmaceutical composition in modified flexible plastic container

ABSTRACT

A ready-to-use injectable, co-solvents (ternary mixture) pharmaceutical composition for the treatment of cardiac conditions and diagnosis applications, comprising methyl-3-[4-(2-hydroxy-3-isopropylamino)propoxy]phenylpropionate hydrochloride (Esmolol hydrochloride), a buffering agent, ethanol and propylene glycol. The ready-to-use injectable, co-solvents (ternary mixture) pharmaceutical composition is capable of being stored in a modified flexible plastic container that may be heat-sterilized without deformation and/or without having the integrity of the closure system being compromised. A method for the manufacture of the ready-to-use injectable, co-solvents (ternary mixture) pharmaceutical composition is also disclosed.

This application is a continuation of U.S. patent application Ser. No.13/840,153, filed Mar. 15, 2013, the disclosure of which is incorporatedherein by reference in its entirety.

SUMMARY OF THE INVENTION

In general, this invention relates to ready-to-use pharmaceuticalcompositions of Esmolol, or a pharmaceutically acceptable salt thereof,that are formulated in co-solvents matrix, stored in flexible plasticcontainer subjected to sterilization via moist-heat autoclaving foradministration to a patient, without further dilution. Further, thecompositions of the formulated as a pharmaceutical composition fortreating/administration to a subject for reduction of heart rate duringcardiac catheterization (i.e. ablation of atrial fibrillation) anddiagnosis of cardiac disease via medical imaging (i.e. coronarycomputerized tomography).

BACKGROUND OF THE INVENTION

Esmolol, the methods for making and for treatment or prophylaxis ofcardiac disorders using such compounds are disclosed in U.S. Pat. Nos.4,387,103 and 4,593,119, incorporated herein by reference. Esmolol andits pharmaceutically acceptable salts, (e.g., hydrochloride salt) andrelated compounds have β-adrenergic blocking activity. It is ashort-acting β-blocker, used in acute care settings to control the heartrate of a patient.

Esmolol is approved treating high blood pressure or rapid heart ratethat occurs during or after surgery. It is also used in treating veryrapid and irregular heart rates in emergency situations in particularly,atrial fibrillation, atrial flutter, or other similar irregular heartrhythms originating in the atria of the heart (the upper chambers).Under certain conditions some healthcare providers have administeredEsmolol and other beta-blockers medication and/or prescribe as“off-label” uses for several coronary-imaging techniques includingdiagnosis of cardiac disease via medical imaging. The use ofbeta-blockers to reduce the heart rate that greatly influences and/orimproves image quality and stenosis detection is well described (see forexample, Ropers D et al. (2006) “Usefulness of multidetector row spiralcomputed tomography with 64×0.6-mm collimation and 330-ms rotation forthe noninvasive detection of significant coronary artery stenoses”.Mollet N R et. al., “Multislice spiral computed tomography coronaryangiography in patients with stable angina pectoris”. J Am Coll Cardiol(2004) 43:2265-2270, Nikolaou K et al. “Accuracy of 64-MDCT in thediagnosis of ischemic heart disease” (2006), Pugliese F et al.“Diagnostic accuracy of noninvasive 64-slice CT coronary angiography inpatients with stable angina pectoris. Eur Radiol 16:575-582 Raff G L,Goldstein J. A. et. al. “Coronary angiography by computed tomography:coronary imaging evolves”. J Am Coll Cardiol. 2007 May 8; 49(18):1830);and other references. The current clinical practice for reducing orinducing lower heart rate to enable coronary computed tomography,quality coronary images is to prescribe long acting beta-blockers, oralmedication of either Metroprolol or Atenolol of about 50-100 mg forseveral hour prior to the schedule procedures. Although, eventually thetarget heart rate of between 50 to 60 beat per minutes would be achievedby multiple combination of tablets and bolus injection of long actingbeta-blockers, there are more drawbacks. Since most of these off-labeluses are not based well designed clinical studies, the formulation,dosing regimen are also not designed to provided the optimal safety andeffectiveness during such procedures. Current Esmolol premixed (vial andbag) presentations are not suitable for several coronary-imagingtechniques due to the drawbacks of the formulation strength and dosingregimen of about 400 microgram per kilogram per minute which wouldmaintain a heart rate of between 50 to 60 beat per minute for shortprocedures lasting between 0.5-1 hour) without heart fluctuation.

Esmolol hydrochloride {methyl3-[4-[2-hydroxy-3-(isopropylamino)propoxy]phenyl]propionate hydrochloride} is a water soluble molecule butwould chemically decomposed via an acid/base catalyzed hydrolysis. Thedecomposition of Esmolol in aqueous environment is sole due to thelabile aliphatic methyl ester group, that degrades into Esmolol acidfree (also known as ASL-8123) {methyl3-[4-[2-hydroxy-3-(isopropylamino)propoxy]phenyl]propionic acid} and methanol. However, in some organicsolvents and/or mixtures thereof, the rate of decomposition of Esmololcan be reduced, which was first disclosed in U.S. Pat. No. 5,017,609 andU.S. App. No. 20080293810. The concept of Premixed or Ready-to-use forEsmolol was first prepared for a concentrate from Brevibloc® 250 mg/mL,10-mL ampoule presentation by Baaske, al. et., (see Baaske, D M.“Stability of esmolol hydrochloride in intravenous solutions.” Amer J ofHosp Pharmacy 51.21 (1994) pp 2693-6). The stability of admixturesolutions of Esmolol Injection was limited to a few days in a PVCinfusion bags. Escobar et. al., and Tiawari et. al., (see U.S. Pat. No.5,017,609 and U.S. App. No. 20080293810) suggested that organic solventshave the ability of reducing the rate of degradation of Esmolol inco-solvent matrix. In 2007, Brevibloc® (Esmolol HCl) Injection, 250mg/mL, 10-mL ampoule was withdrawn for the USA due solely to seriousadverse events via medication errors. However, the chemical stability ofEsmolol HCl and it compatibility to containers has proven to be verychallenging for commercial viability due to its rapid decomposition insolutions. Several formulations of Esmolol HCl have been studied, withthe degradation profile and the stability well characterized. However,the ability to aseptically, terminally sterilize by moist heatsterilization and/or other forms of sterilization of drugs in flexibleplastic containers is still a “black box” especially co-solventformulations with multiple instabilities and sterility issues.

Brevibloc® (Esmolol HCl) Injection, ready-to-use non-isotonic andisotonic formulations of Esmolol are disclosed in (U.S. Pat. Nos.4,857,552, 6,310,094, 6,528,540, and U.S. App. No. 20080293814,20100311738, Baaske, D M. “Stability of esmolol hydrochloride inintravenous solutions.” Amer J of Hosp Pharmacy 51.21 (1994): 2693-6,Rosenberg, L. S. et. al., “An accurate Prediction of the pH Change Dueto Degradation: Correction for a “Produced” Secondary Buffering System.”Pharmaceutical Research 5.8 (1988): 514-517) packaged in either vial orplastic containers, respectively, incorporated herein by reference. Inthe prior art of the above mentioned references, the formulations ofEsmolol in totally aqueous environment were stabilized via pH andself-buffering of the ASL-8123 {methyl3-[4-[2-hydroxy-3-(isopropylamino)propoxy]phenyl]propionic acid}. The rate of degradation of Esmololhydrochloride in totally aqueous formulation is minimized by theconcentration of Esmolol, buffer/self-buffering molecules within a nearpH range. These formulations maintain a reasonable shelf-life, however,upon terminal sterilization in either in glass vials or flexibleplastic, degradation occurs. As a result, prior art formulation packagein vial (small volume parenteral) is prepared aseptically while theflexible plastic container (large volume parenteral) is terminallysterilized.

Currently, the commercialized products of Esmolol in the marketplace arethese ready-to-use isotonic formulations in both flexible plastic andvial presentations. Lui et. al, taught that the ready-to-use isotonicformulations in containers were could be terminally sterilized, withsignificant decomposition. Further, larger volume parenteral injectionsare stored in IntraVia™ flexible plastic, a semi-free of PVC, such asthose disclosed in U.S. Pat. Nos. 5,849,843 and 5,998,019 and aretypically prefer by the national intravenous therapy association andregulatory authorities for being terminal sterilized. Terminalsterilization as a way of reducing microbiological burden and ensurepatient safety of the finished product. However, not all drugformulations, and containers can withstand this technique ofsterilization.

It is well known, described and documented in the pharmaceuticalindustry and any one skilled in the art of formulating co-solventmatrixes in medical plastics (flexible container or multi-layer plasticbags) are not compatible for long-storage due to multi-dimensionalsafety concerns. To name are few potential drawbacks; soften of thepolymers, swallowing/collapse film materials, potential leachable (bothdrug and inks), drug incompatibility and deformation of the containerclosure system. Furthermore, for large volumes parenteral that requirestricter microbiological controls and limits not to exacerbatecross-contaminations to already compromised patients, terminalsterilization is required. Multiple formulations of co-solvents, lipids,exotic encapsulations ranging from small molecules, large, lipophilic,hydrophobic, insoluble molecules, complex formulation with surfacereducing agents, unstable drug substances, etc., have been stored for inmedical plastic containers for small volume parenteral with majorchallenges. The exceptions to aforementioned are foods and cosmeticsformulation that may not be suitable for injection and/or systemiccirculation (drug delivery). An Intralipid formulation in flexiblecontainers is worth noting, where perhaps different polymeric materialsand process are used to claim sterility and non-cross microbiologicalcontamination.

Liu et al. in U.S. Pat. Nos. 6,310,094 and 6,528,540 teach a heatsterilized esmolol formulation packaged in PVC bags. The patents allrely on the absence of ethanol and propylene glycol for success.Previous ready to use formulations had used both ethanol and propyleneglycol as esmolol solubilizers. Prior formulations using these alcoholscould not be successfully heat sterilized.

For over thirty years, Polyvinyl Chloride (PVC) flexible container andits shortcomings has been the commercial choose and the rate-limitingstep for development of premixes in large volume parenteral injection.In recent past, the introduction of new flexible plastic container hasimproved, and issues of water loss, higher levels of extractables andport closure system integrity testing have been resolved. New flexiblecontainer material system and suitable port closures have be designedand more particularly, flexible autoclavable intravenous (IV) containersor bags of non-PVC polyolefin film (e.g., polyethylene or polypropylene)(polymeric materials are disclosed in U.S. Pat. Nos. 4,654,240,5,849,843, 5,783,269, 5,998,019, 6,255,396, 6,461,696, and 6,590,033)nylon, or a composite material, either laminated or co-extrudedstructure (including both monolayer and multilayer structures). It isalso possible to utilize bags composed of laminates where the innerlaminate is inert to the solution such a bags with a polyolefin orpolyethylene vinyl acetate (EVA). Non-PVC flexible plastic containersare considered to be relatively inert and contain low levels ofextractable materials when subjected to aqueous or non-lipophillic drugsubstance/products. However, impart of co-solvents formulation, softnessand deforms non-PVC films, leaching from the film and the heat sealedports and closures becomes unacceptable for storage of certainpharmaceuticals. The non-PVC plastic films provides long shelf life forIV fluid containers, due to low moisture vapor transmission rate, andlow levels extractables terminal sterilization using high temperaturetreatment, i.e., sterilized after filling to deactivate microorganismsinside the containers (e.g., autoclaving) are not suitable for allpharmaceutical formulations. Though, these new materials andtechnologies offered the pharmaceutical industry some flexibility intotally aqueous medias/formulations, additional US or Europeanregulatory requirements on autoclave temperature, accumulativeextractables for laminated or multilayer materials, administrative,injection ports and closure tips (systems) (polymeric materials/portsare disclosed in U.S. Pat. Nos. 4,778,697, 5,976300, 5,590,777,6,869,653 and 7,207,157) have made it desirable for some pharmaceuticalpremixed to be designed in containers with lower moisture vaportransmission rate without the need for overwraps each container. Thechallenges facing premixed formulations are the long-term stability, thefunctionality of the complete assembled container/bag, andnon-predicable adsorption and desorption for the longer term. All priorart for most of commercial flexible plastic container/bag has beenfocused totally aqueous formulations, while co-solvents, surfactantsformulation or proteins are limited.

It is well known, characterized and well documented in literature andseveral patents that commercially available flexible plastic containers,both PVC, non-PVC plastic films are not compatible with certain drugsubstances due to their innate properties. Jenke, D. R. et. al.,“Evaluation of model solvent systems for assessing the accumulation ofcontainer extractables in drug formulations” Int. J. Pharm. 224, 51-60;“Use of binary ethanol/water model solutions to mimic the interactionbetween a plastic material and pharmaceutical formulations” J. Appl.Polym. Sci. 89, 1049-1057; Thiesen, J. et. al. “physico-chemicalstability of docetaxel premix solution and doxcetaxel infusion in PVCand polyolefine containers” Journal of Pharmacy World & Science, vol.21, #3, June 1999, pp 137-141; Trissel L. A. et. al. “Handbook onInjectables drugs, 15th edition, Bethesda, Md.: American Society ofHealth-System Pharmacists, 2009; Moorhatch, P. et. al., “Interactionbetween drugs and plastic intravenous fluid bags. I sorption studies on17 drugs.” Am. J. Hosp. Pharm. 31, 72-78; have used both PVC, non-PVCplastic films, and other plastic elastormers to show that there is anon-specific adsorption/desorption of drugs and drug matrixes fromflexible plastic containers. Thus, formulations of drug substances inconjunction with drug matrixes such co-solvents and/or surfactants arenot stable and they stability cannot be predicted in commerciallyavailable flexible plastic containers. Further, when these flexibleplastic containers are stressed with delivery devices (i.e.sterilization via moist-heat processes), significant decomposition ofthe drug, deformity and leachables of the flexible plastic containersare detected.

DETAILED DESCRIPTION OF THE INVENTION

It is an object of the present invention to provide a co-solvent sterilepremixed pharmaceutical product of esmolol hydrochloride injectable forthe treatment of treatment of cardiac conditions, reducing heart rateduring medical procedures, managing acute atrial fibrillation to preventischemic stroke and improving the quality of diagnosis images ofcoronary computerized tomography.

To this end, the present invention provides a co-solvent sterilepremixed pharmaceutical product stored in a non-PVC flexible plasticcontainer, where the pharmaceutical product has a solution pH between4.5 and 5.5 and contains:

-   -   a. 5 to 40 mg/mL methyl-3-[4-(2-hydroxy-3-isopropylamino)        propoxy]phenylpropionate hydrochloride (esmolol hydrochloride),    -   b. a buffering agent to maintain a solution pH between 4.5 and        5.5,    -   c. 0.1% to 3 w/v % of ethyl alcohol, and    -   d. 0.1% to 3 w/v % of one of propylene glycol or glycerin; and        the pharmaceutical product is contained in a sealed container        and heat-moist sterilized (e.g., autoclaved) for a period of        time sufficient to render the composition sterile.

Thus, an embodiment of the present invention provides a premixed(Ready-to-use), stable, parenteral co-solvents formulation of Esmololhydrochloride and a pharmaceutically acceptable salt with concentrationranging from 5-40 mg/mL, buffered with sodium acetate and/or sodiumtartrate of 0.05 to 2.3 mg/mL, respectively, containing both ethylalcohol and propylene glycol ranging from 0.1 to 3% (weight/volume)each, packaged in a non-PVC plastic container with modified ports andcontainer closure systems and which is terminal sterilization attemperature of at least about 110° C. to 130° C. via autoclaving with adwelling time ranging from 7 to 30 minutes. Esmolol hydrochlorideformulated in co-solvents matrix has been shown in prior art cannotsurvive autoclaving (U.S. Pat. No. 5,017,609 and U.S. App. No.20080293810). The resultants of terminal sterilization are increaseddegradation products and other related esters of Esmolol, which have thesame or similar pharmacological activities. The present invention isstable Esmolol hydrochloride {methyl3-[4-[2-hydroxy-3-(isopropylamino)propoxy]phenyl]propionate hydrochloride} in co-solvents matrix stored inplastic container that subjected to heat-moist sterilization withoutphysical integrity/deformity (“deformity” is been define/means that theflexible plastic container and closure system failed a dye immersiontest in accordance to USP compendia) of the plastic flexibility of theplastic container compromised, and additional essentially free ofleachable material. The surprising findings were linked to increasedstability Esmolol and the composition ratios at lower co-solvents whensubjected to moist-heat sterilization, where the decomposition of theEsmolol after autoclaving range from 0.5 to 2% (Esmolol acid free, alsoknown as ASL-8123). Additionally, formation of the related estersgenerate via heat induce or proposed transesterfication were not presentand were at trace levels after 6 months of storage under acceleratedcondition of 40° C. (“trace levels” means the observed peak were belowthe limit of detection for the HPLC method used which was 0.03%(weight/weight). The prior art U.S. Pat. No. 5,017,609 and App. No.20080293810 provided a teaching of composition ratio ofethanol:propylene glycol:Esmolol (1:1:1) with a concentration range of5-60% by volume ratio and benzyl alcohol, formation of related esters ofEsmolol, but did not include any teaching as to how, when or if theproduct is stored in a flexible plastic container and terminallysterilized. Further, this reference does not teach or guidance effect ofthe stability at lower co-solvents composition and Esmololconcentrations of the related esters of Esmolol as formulated in anon-glass container(s). Since the pH of an infusion can contribute tophlebitis, then it is critical to control the pH of composition duringits shelf life (where acid degradation products affects the solutionmatrix).

In addition, the present invention provides premixed stablepharmaceutical, parenteral co-solvents formulation of Esmololhydrochloride and a pharmaceutically acceptable salt at withconcentration of 5-40 mg/mL, buffered with sodium tartrate of 0.1 to 1.5mg/mL, containing both ethyl alcohol and glycerin ranging from 0.1 to3.0% (weight/volume) each, packaged in a non-PVC plastic container whichis terminal sterilization at temperature of at least about 110° C. to130° C. via autoclaving with a dwelling time ranging from 7 to 30minutes. This compositions of the formulated as a pharmaceuticalcomposition premixed for continuous infusion in subjects undergoingdiagnosis of cardiac disease via medical imaging (i.e. coronarycomputerized tomography) and/or induce heart rate reduction of duringcardiac catheterization such as ablation of atrail fibrillation. Aformulation of Esmolol with a strength of 30 mg/mL dose/infused at about400 microgram per kilogram per minute would maintain and or provide asteady heart rate between 50 to 60 beat per minute for short procedureslasting between 0.5-1 hour) without heart fluctuation. This wouldimprove the images of the coronary computerized tomography and improvethe diagnosis of cardiac disease and treatment.

Esmolol hydrochloride formulated in co-solvents matrix has been shown inprior art cannot survive autoclaving (U.S. Pat. No. 5,017,609 and U.S.App. No. 20080293810). The resultants of terminal sterilization areincreased degradation products and other related esters of Esmolol,which have the same or similar pharmacological activities. The presentinvention is stable Esmolol hydrochloride{methyl3-[4-[2-hydroxy-3-(isopropylamino) propoxy]phenyl]propionatehydrochloride} in co-solvents matrix stored in plastic container thatsubjected to heat-moist sterilization without physicalintegrity/deformity (“deformity” is been define/means that the flexibleplastic container and closure system failed a dye immersion test inaccordance to USP compendia) of the plastic flexibility of the plasticcontainer compromised, and additional essentially free of leachablematerial. The surprising findings were linked to increased stabilityEsmolol and the composition ratios at lower co-solvents when subjectedto moist-heat sterilization, where the decomposition of the Esmololafter autoclaving range from 0.5 to 2% (Esmolol acid free, also known asASL-8123). Additionally, formation of the related esters generate viaheat induce or proposed transesterfication were not present and were attrace levels after 6 months of storage under accelerated condition of40° C. (“trace levels” means the observed peak were below the limit ofdetection for the HPLC method used which was 0.03% (w/w). The prior artU.S. Pat. No. 5,017,609 and App. No. 20080293810 provided a teaching ofcomposition ratio of ethanol:propylene glycol:Esmolol (1:1:1) with aconcentration range of 5-60% by volume ratio and benzyl alcohol,formation of related esters of Esmolol, but did not include any teachingas to how, when or if the product is stored in a flexible plasticcontainer and terminally sterilized. Further, this reference does nottech or guidance effect of the stability at lower co-solventscomposition and Esmolol concentrations of the related esters of Esmololas formulated in a non-glass container(s). Since the pH of an infusioncan contribute to phlebitis, then it is critical to control the pH ofcomposition during its shelf life (where acid degradation productsaffects the solution matrix).

The apparent pH should be between 4.5 and 6.0, or between 4.5 and 5.5,or between 5 and 5.3. Buffering agents are preferably included in thecomposition to maintain the pH at preferred target between 4.5 and 5.5over the course of the shelf-life. Suitable buffering agents are knownin the art, including acetate, tartrate, malate and furmarate. Preferredbuffering agents are sodium acetate and sodium tartrate. The pH can beappropriately adjusted by use of a suitable amount of an appropriateacid or base to achieve the desired pH. Hydrochloric acid is mentionedas a exemplary acid, while sodium hydroxide is mentioned as an exemplarybase.

As described herein, esmolol is contained in the ready-to-usecomposition of the present invention in an amount ranging from 5 to 40mg/mL. In further embodiments of the present invention, the minimumconcentration of esmolol in the ready-to-use composition can be 5 mg/mL,6 mg/mL, 7 mg/mL, 7.5 mg/mL, 8 mg/mL, 9 mg/mL, 10 mg/mL, 15 mg/mL 20mg/mL, 25 mg/mL and the maximum concentration of esmolol can be 40mg/mL, 37.5 mg/mL, 35 mg/mL, 32.5 mg/mL, 30 mg/mL, 27.5 mg/mL, 25 mg/mL,22.5 mg/mL, 20 mg/mL, 17.5 mg/mL or 15 mg/mL, inclusive of all rangesand sub-ranges embraced therein. Exemplary ranges for the esmololconcentration include 5 to 40 mg/mL, or from 7.5 to 35 mg/mL, 10 to 40mg/mL, or from 10 to 35 mg/mL, or from 10 to 30 mg/mL, or from 10 to 25mg/mL, or from 10 to 20 mg/mL, or from 10 to 15 mg/mL.

As described herein, sodium acetate and/or sodium tartrate is containedin the ready-to-use composition of the present invention in an amountranging from 0.05 to 2.3 mg/mL. In further embodiments of the presentinvention, the minimum concentration of sodium acetate and/or sodiumtartrate can be 0.05 mg/mL, 0.1 mg/mL, 0.15 mg/mL, 0.2 mg/mL, 0.25mg/mL, 0.3 mg/mL, 0.35 mg/mL, 0.4 mg/mL, 0.45 mg/mL, 0.5 mg/mL, 0.55mg/mL, 0.60 mg/mL, or 0.65 mg/mL and the maximum concentration of sodiumacetate and/or sodium tartrate can be 2.3 mg/mL, 2.25 mg/mL, 2.2 mg/mL,2.15 mg/mL, 2.1 mg/mL, 2.05 mg/mL, 2.0 mg/mL, 1.95 mg/mL, 1.90 mg/mL,1.85 mg/mL, or 1.8 mg/mL, inclusive of all ranges and sub-rangesembraced therein. Exemplary ranges for the sodium acetate and/or sodiumtartrate concentration include from 0.05 to 2.3 mg/mL, or from 0.1 to2.3 mg/mL, or from 0.2 to 2.3 mg/mL, or from 0.3 to 2.3 mg/mL, or from0.4 to 2.3 mg/mL, or from 0.5 to 2.3 mg/mL, or from 0.6 to 2.2 mg/mL, orfrom 0.65 to 2.1 mg/mL or from 0.65 to 2.0 mg/mL, or from 0.65 to 1.9mg/mL or from 0.65 to 1.8 mg/mL.

As described herein, the ready-to-use composition may further containglacial acetic acid. When present, the glacial acetic acid may becontained in an amount ranging from 0.002 to 0.4 mg/mL. In furtherembodiments of the present invention, the minimum concentration ofglacial acetic acid can be 0.002 mg/mL, 0.0025 mg/mL, 0.003 mg/mL,0.0035 mg/mL, 0.004 mg/mL, 0.0045 mg/mL, or 0.005 mg/mL and the maximumconcentration of glacial acetic acid can be 0.4 mg/mL, 0.375 mg/mL, 0.35mg/mL, 0.325 mg/mL, 0.3 mg/mL, 0.275 mg/mL, or 0.25 mg/mL, inclusive ofall ranges and sub-ranges embraced therein. Exemplary ranges for glacialacetic acid concentration, when present, include from 0.002 to 0.4mg/mL, or from 0.0025 to 0.35 mg/mL, or from 0.003 to 0.3 mg/mL.

As described herein, the ready-to-use composition may further containtartaric acid. When present, the tartaric acid may be contained in anamount ranging from 0.005 to 0.9 mg/mL. In further embodiments of thepresent invention, the minimum concentration of tartaric acid can be0.005 mg/mL, 0.01 mg/mL, 0.015 mg/mL, 0.02 mg/mL, 0.025 mg/mL, 0.03mg/mL, or 0.035 mg/mL and the maximum concentration of tartaric acid canbe 0.9 mg/mL, 0.85 mg/mL, 0.8 mg/mL, 0.75 mg/mL, 0.7 mg/mL, 0.65 mg/mL,or 0.6 mg/mL, inclusive of all ranges and sub-ranges embraced therein.Exemplary ranges for tartaric acid concentration, when present, includefrom 0.005 to 0.9 mg/mL, or from 0.015 to 0.85 mg/mL, or from 0.02 to0.8 mg/mL, or from 0.25 to 0.75 mg/mL.

As described herein, ethyl alcohol (i.e., ethanol) is contained in theready-to-use composition of the present invention in an amount rangingfrom 0.1 to 3% (all percentages herein under are weight/volume). Infurther embodiments of the present invention, the minimum concentrationof ethyl alcohol can be 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.35%, 0.4%,0.45%, or 0.5% and the maximum concentration of ethyl alcohol is 3%,2.75%, 2.5%, 2.25%, 2%, 1.75%, 1.5%, 1.25%, 1%, 0.75%, or 0.5%,inclusive of all ranges and sub-ranges embraced therein. Exemplaryranges for the ethyl alcohol concentration include from 0.1 to 3%, orfrom 0.1 to 2.5%, or from 0.1 to 2%, or from 0.1 to 1.5%, or from 0.1 to1%, or from 0.1 to 0.5%, or from 0.15 to 3%, or from 0.15 to 2.5%, orfrom 0.15 to 2%, or from 0.15 to 1.5%, or from 0.15 to 1%, or from 0.15to 0.5%.

Where propylene glycol is contained in the ready-to-use composition ofthe present invention it is present in an amount ranging from 0.1 to 3%(all percentages herein under are weight/volume). In further embodimentsof the present invention, the minimum concentration of propylene glycolcan be 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, or 0.5% andthe maximum concentration of ethyl alcohol is 3%, 2.75%, 2.5%, 2.25%,2%, 1.75%, 1.5%, 1.25%, 1%, 0.75%, or 0.5%, inclusive of all ranges andsub-ranges embraced therein. Exemplary ranges for the propylene glycolconcentration include from 0.1 to 3%, or from 0.1 to 2.5%, or from 0.1to 2%, or from 0.1 to 1.5%, or from 0.1 to 1%, or from 0.1 to 0.5%, orfrom 0.15 to 3%, or from 0.15 to 2.5%, or from 0.15 to 2%, or from 0.15to 1.5%, or from 0.15 to 1%, or from 0.15 to 0.5%.

In yet another alternative invention, provides a rigid plastic container(vial and bottle configuration) with teflon coated rubber stoppers canbe used as closure system suitable for storing premixed solution ofEsmolol Injection with co-solvents matrix which is subjected totypically product sterilization by steam sterilization autoclaving, 121°C. for a about 15 minutes) without altering the thermal properties vialand/or bottle, and maintaining the integrity container. The primarypolymeric container was made-up of Cryovac's™ M312A film ofmultiple-layers of at least 5 poly, but the ports and closure systemwere modified to provide resistance to polymer softening, a moisturebarrier, lower leachables and functionality closure system during thestability phase and shelf life of the formulation (“functionality” ofthe closure system is been define as the spiking of the closure systemto enable flow using an infusion sets). The modifications to flexibleplastic container ports and closure system were necessary due thedrawbacks observed when co-solvent formulations of Esmolol were stresscommercially available flexible plastic containers (bags). Thesedrawbacks of the unmodified bags were failure of container closureintegrity in accordance with USP dye immersion, higher levels ofleachables, and collapse of port access for an IV spike (infusion setspike) to puncture membrane. The ports and the closure system preferablyuses commerciality available polymers, elastomers etc., theadministrative and additive ports were made off external coextrudedlayer consists of synthetic thermoplastic rubber (Raumedic SRT320)ranging from about 20 to 30% based on an elastomer modifiedpolypropylene. While the internal coextruded layer (PE770) of not morethan 50% in composition consists of ethylenvinyl acetate without anyfurther additives (EVA). The tubing ports are made of two-layermaterials, which can withstand both terminal sterilization andco-solvent matrix. Furthermore, the twist-off compositions were made ofpolyproplene Granuflex® 4489 between 70-80% and Granuflex®4371 15-20%.However, other polymers stable, low leachables, and without physicaldeformation as defined previously in the presence of the esmololsolution and to heat sterilization may also be used for the ports andclosure assemblies, referred to as modified ports and closures.

Commercially available flexible plastic containers (bags) such as Excel®(Braun Company), Visiv® (Hospira), Necexl® (Sealed Air), Intervia®(Baxter), Technoflex, etc., for pharmaceutical formulation or medicalliquids are assemble of different plastic materials of differentproperties, thermal resistance and functionalities. They are typicallydesigned and tested mostly for aqueous formulations admixtures, premixedor ready-to-use pharmaceutical products. Still the combination of theco-solvents and drug composition subjected to further heat sterilizationcan adversely effect, plastic materials, sealing integrity and thesolutions contained therein unless they are maintained at certainconditions.

In another alternative invention, provides a flexible plastic containerwith modified ports and closure system suitable for storing premixedsolution of Esmolol Injection with co-solvents matrix which is subjectedto typically product sterilization by steam sterilization (autoclaving,121° C. for a about 15 minutes) without altering the thermal propertiesof the film layers, ports and closure system as well as maintaining theintegrity container. The primary polymeric materials which may be usedinclude: polysulfone, polycarbonate, polypropylene, polyethylene (LDPEor HDPE), ethylene/propylene copolymers, polyolefins, acrylic-imidecopolymers, polyester (e.g. PET, PEN and the like), Teflon, Nylon,acetal (Delrin), polymethylpentene, PVDC, ethylvinylacetate,AN-copolymer etc. The premixed stable pharmaceutical, parenteralco-solvents formulation of Esmolol hydrochloride and a pharmaceuticallyacceptable salt at with concentration of 5-40 mg/mL, buffered withsodium tartrate of 0.1 to 1.5 mg/mL, containing both ethyl alcohol andglycerin ranging from 0.1 to 3.0% (weight/volume) each, packaged in anon-PVC plastic container with modified ports and container closuresystems and which is terminal sterilization at temperature of at leastabout 110° C. to 130° C. via autoclaving with a dwelling time rangingfrom 7 to 30 minutes.

Where glycerin is contained in the ready-to-use composition of thepresent invention it is present in an amount ranging from 0.1 to 3% (allpercentages herein under are weight/volume). In further embodiments ofthe present invention, the minimum concentration of glycerin can be0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, or 0.5% and themaximum concentration of glycerin is 3%, 2.75%, 2.5%, 2.25%, 2%, 1.75%,1.5%, 1.25%, 1%, 0.75%, or 0.5%, inclusive of all ranges and sub-rangesembraced therein. Exemplary ranges for the glycerin concentrationinclude from 0.1 to 3%, or from 0.1 to 2.5%, or from 0.1 to 2%, or from0.1 to 1.5%, or from 0.1 to 1%, or from 0.1 to 0.5%, or from 0.15 to 3%,or from 0.15 to 2.5%, or from 0.15 to 2%, or from 0.15 to 1.5%, or from0.15 to 1%, or from 0.15 to 0.5%.

Exemplary embodiments of the formulation of the present inventioninclude:

-   -   A formulation for 10 mg/mL esmolol (2.5 g/250 mL) containing 1%        esmolol (10 mg/mL) plus 1% ethyl alcohol (˜10 mg/mL) plus 1%        propylene glycol (˜10 mg/mL) in sodium acetate buffer.    -   A formulation for 20 mg/mL esmolol (2.0 g/100 mL) containing 2%        esmolol (20 mg/mL) plus 0.5% ethyl alcohol (˜5 mg/mL) plus 0.5%        propylene glycol (˜5 mg/mL) in sodium acetate buffer.    -   A formulation for 30 mg/mL esmolol (1.5 g/50 mL) containing 3%        esmolol (30 mg/mL) plus 0.1% ethyl alcohol (˜1 mg/mL) plus 0.2%        glycerin (˜2 mg/mL) in sodium tartrate buffer.

An advantage of the present invention is that, unlike prior artcompositions of Esmolol, the formulation does not form degredants ofother related esters of Esmolol.

A further advantage of the present invention to provide a method ofreducing pharmaceutical active substance wastage in formulation ofEsmolol usage, which method comprises of titrating to the desire effectwherein the composition requires no dilution prior to administration.

Another advantage of the present invention is that it offers theflexibility and use for the treating/administration to a subject forreduction of heart rate during cardiac catheterization (i.e. ablation ofatrial fibrillation) and improved the quality of diagnosis of cardiacdisease via medical imaging (i.e. coronary computerized tomography).

Still another advantage of the present invention is that it providessterile, read-to infused Esmolol compositions that contain lessexcipients and are simpler for the formulation strength and dosingregimen to be infused at about 200-400 microgram per kilogram per minutewhich maintains a heart rate of between 50 to 60 beat per minute forshort procedures lasting between 0.5-1 hour, without heart fluctuation.

In addition, the flexible plastic container with the modifiedadministrative and injection ports with closure system used forpackaging the ready-to-use premix Esmolol have extremely low levels ofextractable and leachable materials and thus a safer product during theshelf life of the product.

The present invention also provides a method of controlling bradycardiaand/or controlling hypotension in the diagnosis of cardiac conditionsusing computerized cardiac tomography in humans comprising administeringto a subject in need thereof an effective amount of the pharmaceuticalproduct described herein above.

The dosing and route of administration can be readily ascertained by theclinical physician. It is contemplated that the effective amount andadministration route of a composition will depend on a number offactors, including by not limited to the age of the patient, immunestatus, race, and sex of the patient, and the severity of thecondition/disease, and the past medical history of the patient, andalways lies within the sound discretion of the administering physician.

By way of example only, the following exemplary administrationembodiments are provided:

-   -   For the control of high heart rate and hypertension,        administration is preferably intravenous using a peripheral        and/or central venous access, with a loading dose of 0.5        milligrams/kg infused over 1 minute period of time, for a 70 kg        patient, followed by a maintenance infusion rate of 50        mcg/kg/min to the desired therapeutic effect.    -   For controlled bradycardia, the administration is preferably        intravenous using a peripheral and/or central venous access,        with a loading dose of 1 milligrams/kg infused over 1 minute        period of time, for a 70 kg patient, followed by a maintenance        infusion rate of 200 mcg/kg/min to the desired therapeutic        effect.

The present invention further provides methods of preparing thepharmaceutical product described herein above.

One embodiment of the method of preparing the pharmaceutical product,entails:

-   -   preparing a composition comprising:        -   a. 5 to 40 mg/mL methyl-3-[4-(2-hydroxy-3-isopropylamino)            propoxy]phenylpropionate hydrochloride (esmolol            hydrochloride),        -   b. a buffering agent to maintain a solution pH between 4.5            and 5.5,        -   c. 0.1% to 3 w/v % of ethyl alcohol and        -   d. 0.1% to 3 w/v % of one of propylene glycol or glycerin;    -   adding the composition to a non-PVC flexible plastic container        as defined above;    -   sealing the container; and    -   subjecting the sealed container to heat-moist sterilization for        a period of time sufficient to render the composition sterile        thereby forming said pharmaceutical product.

Another embodiment of the method of preparing the pharmaceuticalproduct, entails:

-   -   preparing in a non-PVC flexible plastic container as defined        above a composition comprising:        -   a. 5 to 40 mg/mL methyl-3-[4-(2-hydroxy-3-isopropylamino)            propoxy]phenylpropionate hydrochloride (esmolol            hydrochloride),        -   b. a buffering agent to maintain a solution pH between 4.5            and 5.5,        -   c. 0.1% to 3 w/v % of ethyl alcohol, and        -   d. 0.1% to 3 w/v % of one of propylene glycol or glycerin;    -   sealing said container; and    -   subjecting the sealed container to heat-moist sterilization for        a period of time sufficient to render the composition sterile        thereby forming said pharmaceutical product.

Within these embodiments, it is preferred that heat-moist sterilizationis autoclaving.

Within these embodiments, it is preferred that the autoclavingtemperature range from 110 to 130° C. The autoclaving temperature can beat a minimum temperature of 111° C., 112° C., 113° C., 114° C., 115° C.,116° C., 117° C., 118° C., 119° C., or 120° C. and the maximumtemperature can be 130° C., 129° C., 128° C., 127° C., 126° C., 125° C.,124° C., 123° C., 122° C., 121° C., or 120° C., inclusive of all rangesand sub-ranges embraced therein. Exemplary ranges for the autoclavingtemperature include from 110 to 130° C., or from 115 to 125° C.

Within these embodiments, it is preferred that the autoclaving timerange from 7 to 60 minutes. The autoclaving time can be at a minimum of7 minutes, 9 minutes, 11 minutes, 13 minutes or 15 minutes and themaximum autoclaving time can be 60 minutes, 45 minutes 30 minutes, 28minutes, 26 minutes, 25 minutes, 24 minutes, 22 minutes, or 20 minutes,inclusive of all ranges and sub-ranges embraced therein. Exemplaryranges for the autoclaving time include from 7 to 60 minutes, or from 8to 45 minutes, or from 9 to 30 minutes, or from 10 to 25 minutes, orfrom 15 to 20 minutes.

The terms “premix” or “premixture” as used herein refers to apharmaceutical formulation that does not require reconstitution ordilution prior to administration to a patient. For example, in contrastto non-premixed formulations of esmolol, the premixed compositionsprovided herein are suitable for administration to a patient withoutdilution by, for example, a clinician, hospital personnel, caretaker,patient or any other individual.

In certain embodiments, the compositions of the present invention can beformulated as “ready to use” compositions which refer to premixedcompositions that are suitable for administration to a patient withoutdilution. For example, in certain embodiments, the compositions of thepresent invention are “ready to use” upon removing the compositions froma sealed container or vessel.

The above written description of the invention provides a manner andprocess of making and using it such that any person skilled in this artis enabled to make and use the same, this enablement being provided inparticular for the subject matter of the appended claims, which make upa part of the original description.

As used herein, the phrases “selected from the group consisting of,”“chosen from,” and the like include mixtures of the specified materials.

Where a numerical limit or range is stated herein, the endpoints areincluded. Also, all values and subranges within a numerical limit orrange are specifically included as if explicitly written out.

The above description is presented to enable a person skilled in the artto make and use the invention, and is provided in the context of aparticular application and its requirements. Various modifications tothe preferred embodiments will be readily apparent to those skilled inthe art, and the generic principles defined herein may be applied toother embodiments and applications without departing from the spirit andscope of the invention. Thus, this invention is not intended to belimited to the embodiments shown, but is to be accorded the widest scopeconsistent with the principles and features disclosed herein.

Having generally described this invention, a further understanding canbe obtained by reference to certain specific examples, which areprovided herein for purposes of illustration only, and are not intendedto be limiting unless otherwise specified.

EXAMPLES

The following example compositions and method of manufacture of Esmololready-to-use (premixed) containing 5-40 mg/mL of Esmolol HCl, ethanol,propylene glycol and/or glycerin have been provided to furtherillustrate the invention, but should not be construed as limiting itsscope.

Example 1

Ingredient Concentration, mg/mL Esmolol 10-30 mg/mL Sodium AcetateTrihydrate 0.68-2.04 mg/mL Glacial Acetic Acid 0.0026 mg/mL EthylAlcohol, USP 0.15-1.5% Propylene glycol USP 0.15-1.5% Water forInjection, USP Qs Target pH 5.2

Charge the formulation tank with about eighty percent (80%) of the finalvolume Water for Injection while sparging with nitrogen (dissolvedoxygen content must be less than 12 ppm). Maintain a constant mixedduring the compounding process formulation vessel.

Glacial acetic acid is added to the formulation vessel and dissolvedcompletely. Further, sodium acetate is added to the formulation vesseland dissolved completely. The solution is then adjusted to pH 5.2 with 1N sodium hydroxide or hydrochloric acid. The esmolol HCl drug substanceis added to the formulation vessel and dissolved completely.

Both propylene glycol and ethyl alcohol are added to the formulationvessel and dissolved completely. The solution is brought to final volumewith water for injection and mixed. The bulk product is filtered througha 0.45 pre-filter and 0.2 μm filter and filled into 250 mL modifiedflexible plastic container and sealed. The products are then loaded intoan autoclaving sterilizer and sterilized at 121° C. for 20 minutes.After cool to ambient conditions, these bags are sealed in aluminum foiloverpouches and subjected to stability studies.

Example 2

Ingredient Concentration, mg/mL Esmolol 10-30 mg/mL Sodium Tartratedihydrate 0.35-1.80 mg/mL Tartaric Acid 0.025-0.76 mg/mL Ethyl Alcohol,USP 0.15-0.5% Propylene glycol USP 0.15-0.5% Water for Injection, USP QsTarget pH 5.2

Charge the formulation tank with about eighty percent (80%) of the finalvolume water for Injection while sparging with Nitrogen (dissolvedoxygen content must be less than 12 ppm). Maintain a constant mixedduring the compounding process formulation vessel.

Glacial acetic acid is added to the formulation vessel and dissolvedcompletely. Further, sodium acetate is added to the formulation vesseland dissolved completely. The solution is then adjusted to pH 5.2 with 1N sodium hydroxide or hydrochloric acid. The esmolol HCl drug substanceis added to the formulation vessel and dissolved completely.

Both propylene glycol and ethyl alcohol are added to the formulationvessel and dissolved completely. The solution is brought to final volumewith water for injection and mixed. The bulk product is filtered througha 0.45 pre-filter and 0.2 μm filter and filled into 250 mL modifiedflexible plastic container and sealed. The products are then loaded intoan autoclaving sterilizer and sterilized at 121° C. for 20 minutes.After cool to ambient conditions, these bags are sealed in aluminum foiloverpouches and subjected to stability studies.

Example 3

Ingredient Concentration, mg/mL Esmolol 10-30 mg/mL Sodium Tartratedihydrate 0.35-1.80 mg/mL Tartaric Acid 0.025-0.76 mg/mL Ethyl Alcohol,USP 0.15-1% Glycerin, USP 0.15-2% Water for Injection, USP Qs Target pH5.2

Charge the formulation tank with about eighty percent (80%) of the finalvolume Water for Injection while sparging with Nitrogen (dissolvedoxygen content must be less than 12 ppm). Maintain a constant mixedduring the compounding process formulation vessel.

Glacial acetic acid is added to the formulation vessel and dissolvedcompletely. Further, sodium acetate is added to the formulation vesseland dissolved completely. The solution is then adjusted to pH 5.2 with 1N sodium hydroxide or hydrochloric acid. The Esmolol HCl drug substanceis added to the formulation vessel and dissolved completely. Bothpropylene glycol and ethyl Alcohol are added to the formulation vesseland dissolved completely. The solution is brought to final volume withWater for Injection and mixed. The bulk product is filtered through a0.45 pre-filter and 0.2 μm filter and filled into 250 mL modifiedflexible plastic container and sealed. The products are then loaded intoan autoclaving sterilizer and sterilized at 121° C. for 20 minutes.After cool to ambient conditions, these bags are sealed in aluminum foiloverpouches and subjected to stability studies.

Example 4

Exemplary specific formulations of the present invention include:Ingredient Ex. 4-a Ex. 4-b Esmolol HCl 10.0 mg/mL 20.0 mg/mL SodiumAcetate 0.68 mg/mL 0.68 mg/mL Trihydrate Glacial Acetic Acid 0.30 mg/mL0.30 mg/mL Ethanol   10 mg/mL   10 mg/mL Propylene Glycol   10 mg/mL  10 mg/mL Hydrochloric Acid As required As required Sodium Hydroxide Asrequired As required Water for Injection Q.S. (quantity sufficient) Q.S.(quantity sufficient) Appearance Clear and Colorless Clear and ColorlessApparent pH 4.9 4.8 Extractable Volume 255 mL 102 mL

Example 5

The stability studies were performed under 25° C. and 40° C. forflexible containers as mandated by the International Conference onHarmonization (ICH) guidance. At a pre-determined stability intervals,bags of each solution were tested for pH, potency, physical appearanceand particulate matter. The concentration of the drug and the relateddegradation products was determined by a high performance liquidchromatographic (HPLC) method. The data gathered to date for the Esmololready-to-use pharmaceutical compositions described herein demonstratesabout 5% drop in drug concentration under 25° C. condition for 12 monthsand about 4.5% formation of impurities. However under acceleratedcondition (at 40° C.) for 6 months the drug concentration dropped byabout 8% with a corresponding decomposition products of about 7.5% Basedon published literature by Rosenberg, L. S. et. al., “An accuratePrediction of the pH Change Due to Degradation: Correction for a“Produced” Secondary Buffering System.” Pharmaceutical Research 5.8(1988): 514-517, activation energies for Esmolol decompositions is about19-21.5 Kcal/mol. Under these conditions (assumption Ea=19 Kcal/mol)from the 40° C. predict to a product shelf life of 24 months expirationat under 25° (see, e.g., Connors, K. A., et al., Chemical Stability ofPharmaceuticals, A Handbook for Pharmacists, John Wiley & Sons, 2d ed.1986. Typically, when a pharmaceutical compositions can maintained suchhigher drug concentration at room temperature for at least 12 months,the term “stable formulation”, is implied as used herein, meansremaining in a state or condition that is suitable for administration toa patient.

The stability results are summarized as follows to affirm the productstability:

Stability of 2.5 g/250 mL bags stored at various temperatures/relativehumidity (RH) and times was evaluated using a composition for 10 mg/mLesmolol (2.5 g/250 mL) which contained 1% esmolol (10 mg/mL) plus 1%ethyl alcohol (˜10 mg/mL) plus 1% propylene glycol (˜10 mg/mL) in sodiumacetate buffer.

Stability of 2.5 g/250 mL Bags Stored at Various Temperatures/RH andTimes Particulate Matter*** Percent ASL- Propyl Ethyl Visual ParticlesParticles Test Time Remaining pH 8123 Esters Ester Inspection ≧3 mm ≧25mm 25° C./35% RH* Pre 101.2 4.9 0.03 <0.03 <0.03 CCSFP** 0 O autoclavingInitial 100.31 4.9 1.30 <0.03 <0.03 CSFP 0 1 3 months 100.0 4.9 2.13<0.03 <0.03 CSFP 0 1 6 months 99.68 4.8 2.87 <0.03 <0.03 CSFP 0 0 9months 98.43 4.8 3.72 <0.03 <0.03 CSFP 1 2 12 months 96.86 4.8 4.44<0.03 <0.03 CSFP 0 2 40° C./15% RH* Pre 101.2 4.9 0.03 <0.03 <0.03 CSFP0 o autoclaving Initial 100.31 4.9 1.30 <0.03 <0.03 CSFP 0 1 1 months99.27 4.9 2.32 <0.03 <0.03 CSFP 0 2 2 months 98.13 4.8 3.34 <0.03 <0.03CSFP 0 0 3 months 96.23 4.8 4.36 <0.03 0.03 CSFP 1 2 6 months 93.35 4.77.51 0.04 0.08 CSFP 0 1 *The storage temperature and humidityconditions. RH = Relative Humidity **CCSFP: clear colorless solutionfree of particles. ***Particulate Matter is measured particles per mL

Stability of 2.5 g/250 mL bags stored at various temperatures/relativehumidity (RH) and times was evaluated using a composition for 30 mg/mLesmolol (1.5 g/50 mL) which contained 3% esmolol (30 mg/mL) plus 0.1%ethyl alcohol (˜1 mg/mL) plus 0.2% glycerin (˜2 mg/mL) in sodiumtartrate buffer.

Stability of 3.0 g/100 mL Bags Stored at Various Temperatures/RH andTimes Particulate Matter*** Percent ASL- Glycerin Ethyl Visual ParticlesParticles Test Time Remaining pH 8123 Esters Ester Inspection ≧600 mm≧6000 mm 25° C./35% RH* Pre 101.2 5.1 0.15 <0.03 <0.03 CCSFP** 3 100autoclaving Initial 100.31 5.0 0.80 <0.03 <0.03 CSFP 1 190 3 months100.0 5.0 1.54 <0.03 <0.03 CSFP 0 80 6 months 101.28 5.1 1.28 <0.03<0.03 CSFP 0 170 9 months 98.43 5.0 2.32 <0.03 <0.03 CSFP 3 100 12months 96.86 4.8 3.14 <0.03 <0.03 CSFP 2 12 40° C./15% RH* Pre 101.2 5.10.15 <0.03 <0.03 CSFP 3 10 autoclaving Initial 100.31 5.0 0.80 <0.03<0.03 CSFP 1 19 1 months 99.27 4.9 1.32 <0.03 <0.03 CSFP 0 11 2 months98.13 4.8 1.94 <0.03 <0.03 CSFP 0 8 3 months 96.23 4.7 2.56 <0.03 0.03CSFP 3 8 6 months 93.35 4.7 5.98 <0.03 0.03 CSFP 2 14 *The storagetemperature and humidity conditions. RH = Relative Humidity **CCSFP:clear colorless solution. ***Particulate Matter is measured particlesper bag

What is claimed is:
 1. A co-solvent sterile premixed pharmaceuticalproduct stored in a non-PVC flexible plastic container, wherein saidpharmaceutical product has a solution pH between 4.5 and 5.5 andcomprises: a. 5 to 40 mg/mL methyl-3-[4-(2-hydroxy-3-isopropylamino)propoxy]phenylpropionate hydrochloride (esmolol hydrochloride), b. abuffering agent to maintain a solution pH between 4.5 and 5.5, c. 0.1%to 3 w/v % of ethyl alcohol, and d. 0.1% to 3 w/v % of one of propyleneglycol or glycerin; and wherein said pharmaceutical product is containedin a sealed container and heat-moist sterilized for a period of timesufficient to render the composition sterile.
 2. The pharmaceuticalproduct of claim 1, wherein the non-PVC flexible plastic containercomprises a 3-7 multi-layer, polyolefin based co-extruded film, non-PVC,latex free, plasticizer free, tubing ports are made of a two layermaterial that is suitable for terminal sterilization.
 3. Thepharmaceutical product of claim 2, wherein the polyolefin basedco-extruded film is selected polypropylene, cycloolefin, polyethyleneand copolymerized ethylene vinyl acetate.
 4. The pharmaceuticalcomposition of claim 1, wherein the non-PVC flexible plastic containercomprises modified tubing ports and closure systems made of a materialthat is suitable for terminal sterilization.
 5. The pharmaceuticalproduct of claim 1, wherein the buffering agent comprises at least oneof acetate, tartrate, malate and furmarate.
 6. The pharmaceuticalproduct of claim 1, wherein the buffering agent is sodium acetate. 7.The pharmaceutical product of claim 1, wherein the buffering agent issodium tartrate.
 8. The pharmaceutical product of claim 1, wherein theesmolol hydrochloride is contained in an amount ranging from 10 to 30mg/mL.
 9. The pharmaceutical product of claim 1, wherein (d) ispropylene glycol.
 10. The pharmaceutical product of claim 1, wherein (d)is glycerin.
 11. The pharmaceutical product of claim 1, wherein thecontainer is made of a rigid or flexible plastic container and exhibits(i) less than a 2% decrease in the concentration of Esmolol orpharmaceutically acceptable salt thereof after autoclaving (terminalsterilization) and (ii) having formation of related Esmolol esters lessthan about 0.5% (ii) having co-solvents composition between 0.15% to 5%stored in a non-PVC flexible plastic container and comprising wherein inat least the inner most layer which contacts the esmolol solutioncomprises a copolymer of ethylene and vinyl acetate.
 12. A method ofcontrolling bradycardia and/or controlling hypotension in the diagnosisof cardiac conditions using computerized cardiac tomography in humanscomprising administering to a subject in need thereof an effectiveamount of the pharmaceutical product of claim
 1. 13. A method ofpreparing a pharmaceutical product of claim 1, comprising preparing acomposition comprising: a. 5 to 40 mg/mLmethyl-3-[4-(2-hydroxy-3-isopropylamino) propoxy]phenylpropionatehydrochloride (esmolol hydrochloride), b. a buffering agent to maintaina solution pH between 4.5 and 5.5, c. 0.1% to 3 w/v % of ethyl alcohol,and d. 0.1% to 3 w/v % of one of propylene glycol or glycerin; addingsaid composition to a non-PVC flexible plastic container; sealing saidcontainer; and subjecting the sealed container to heat-moiststerilization for a period of time sufficient to render the compositionsterile thereby forming said pharmaceutical product.
 14. The method ofclaim 13, wherein said heat-moist sterilization is autoclaving.
 15. Themethod of claim 14, wherein said autoclaving is at a temperature rangingfrom 110 to 130° C. for a period of time ranging from 7 to 60 minutes.16. A method of preparing a pharmaceutical product of claim 1,comprising preparing in a non-PVC flexible plastic container acomposition comprising: a. 5 to 40 mg/mLmethyl-3-[4-(2-hydroxy-3-isopropylamino) propoxy]phenylpropionatehydrochloride (esmolol hydrochloride), b. a buffering agent to maintaina solution pH between 4.5 and 5.5, c. 0.1% to 3 w/v % of ethyl alcohol,and d. 0.1% to 3 w/v % of one of propylene glycol or glycerin; sealingsaid container; and subjecting the sealed container to heat-moiststerilization for a period of time sufficient to render the compositionsterile thereby forming said pharmaceutical product.
 17. The method ofclaim 16, wherein said heat-moist sterilization is autoclaving.
 18. Themethod of claim 17, wherein said autoclaving is at a temperature rangingfrom 110 to 130° C. for a period of time ranging from 7 to 60 minutes.